1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and anti-tumor compounds. More specifically, the present invention relates to the asymmetric synthesis of (S,R,R)-(−)-actinonin and derivatives and analogs thereof and their uses as anti-tumor agents.
2. Description of the Related Art
(S,S,R)-(−)-Actinonin (1), was first isolated by Green and Singh from the Malayan strain of Actinomycete, Streptomyces sp. Cutter 12 (N.C.I.B. 8845) (FIG. 1). It has been shown that actinonin exhibits antibiotic and anti-tumor properties (1-7). Studies have demonstrated that actinonin exhibits cytotoxicity towards tumor cell lines in vitro (4). Furthermore, actinonin induces G1 arrest and apoptosis in human leukemia and lymphoma cells. It also treats AKR leukemia in AKR mice with minimal toxicity.
Although actinonin is commercially available and usually extracted from Actinomycete and Streptomyces bacteria, specifically Streptomyces roseopallidus (9, 10), the yield of compound derived is miniscule. For example, out of a typical ten day culture that yields eleven liters of filtrate, only 146 mg of pure actinonin are isolated. Currently, actinonin is synthesized by either of two synthetic schema. In Ollis' 1975 synthetic method, the synthesis of actinonin is non-stereoselective and the diastereomers have to be separated; difficult process producing small yields (11). Davies' 1992 synthesis is stereoselective and represents the first asymmetric synthesis of (−)-actinonin. An Fe(II)-based chiral auxiliary is used to introduce chirality at the α-position of a carboxylic acid (13,14). However, this process causes disposal problems and therefore commercialization of the synthetic (−)-actinonin is doubtful. It is therefore necessary to develop a method for multi-gram synthesis of actinonin for further testing in various cancer cell lines and for animal studies.
The prior art is deficient in the lack of effective means of asymmetically synthesizing (S,R,R)-(−)-actinonin, its derivatives and its analogs for use as anti-tumor agents. The present invention fulfills this long-standing need and desire in the art.